How cell growth and proliferation are coordinated with metabolism and the metabolic state of a cell is an important unresolved question that is critical to understanding the metabolic alterations that contribute to cancer. Cancer cells frequently exhibit a highly glycolytic metabolism and consume substantial quantities of glucose to promote proliferation. However, the mechanisms by which glucose and carbon source availability are sensed by a cell as a measure of proliferative capacity remain controversial and poorly understood. Despite renewed interest in cancer metabolism, it has been unclear which aspect of cellular metabolism might represent a realistic, targetable vulnerability of tumors but not normal cells. We recently discovered that acetyl-CoA represents the key metabolite of carbon sources that functions as a critical metabolic signal for growth. Upon entry into growth, cells upregulate the production of acetyl- CoA which consequently induces the acetylation of histones specifically at those genes important for growth. As such, acetyl-CoA enables the expression of these growth genes and thus commitment to proliferation. Preliminary data suggest that a similar metabolic growth control mechanism exists in mammalian cells. These and other considerations have led to the realization that particular enzymes and proteins may play critical roles in fueling the acetyl-CoA- induced growth response pathway. The goal of this proposal is to comprehensively investigate the feasibility of targeting aspects of acetyl-CoA metabolism for the discovery of anti-cancer therapeutics.